Method of concentration



sept. 6, w49. C. DUNN E-AL- 2,481,092

METHOD OF CNCENTRATION Filed Aug. 20, 1945 SohrHon of lNVEINTOiLS '.Clarence L.. Dunn MoTT 5oudera,dr. Comahue Groei' BY Tuanz A-r'rozNLY MM.-

Patented Sept. 6, 1949 Clarence L. Dunn, Berkeley,

Piedmont; andV Corneliusl to ShelfDevelopment Com-nl Calif., a corporatio'nwf Calif., assgnors Dany, ySan Francisco,

Delaware Mott Senders, J r.;

Groot, Berkeley,

Application August 20, 1945, Serial No. 611,650 12 Claims. (Cl. 260-302)` This invention relates to a process for recovering and concentrating `unstable organic compounds; More particularly; it deals with the transfer of unstable organic compounds between diiierent liquid media.y Still more particularly, it deals with the transfer of unstable acid-acting organic compounds from an organic solvent solution to an aqueous medium which is susceptible to ready handling and concentration.

It is an object of this invention to recover and concentrate-simply,effectively, quickly and economically--unstable acid-acting organic compounds from their organic solutions. Another object is to` avoid the use ofa slurry in producing a salt of a relativelywater-insoluble'base and an unstable organicacd. Another object is to concentrate quickly and economically a liquid medium possessing a low content of a relatively noninsoluble inorganic salt of an antibiotic; such as penicillin. Another object'is to produce a relatively stablesalt of penicillin; Another object is to concentrate quickly and efficiently antibiotics in highly diluted solutions. Another object is to extract an unstable acid-acting organic compound from organic solvent solutions with a true aqueous solution of an alkaline earth metal base and concentrateA the resulting aqueous phase of said compounds. by recirculation through a flash evaporator, prior to sublimation to dryness; Still other objects of this invention will appear from time to time in the' following description.

Some of the unstable organic compounds comprehendedby this'invention are: ketocarboxylic acids, acrylic and alkyl acrylic "acids, picric acid, certain hormones, certainvitamins, and certain antibiotics such as penicillin. For a discussion of the sources of antibiotic substances, reference is madeto Fndeavory (Kynock Press, London) Vol. 3, No. 9, January,f1944; pp. 3-14.

As illustrative of the application of this method, reference` will now` .be made to the .treatment of penicillin.

In order to separate `penicillin from mold and/or impurities naturally associated with it, it is customary to go through an extraction process with an organic solvent for penicillin whereby a solution of relatively pure penicillin in'thesolvent is eventually obtained. In the last step of the recovery process, the penicillin is transferred back intowater in the .form of'its sodium salt by extraction from the solvent solution with an aque ous sodium bicarbonate: solution. Heretoiore, it has been customary to charge the iinal aqueous solution of penicillin,saltlintdampules and then sublime the bulk of the watertherefrmat Very low subatmospheric pressure' at or belowa temperature of about -0TC. However; this procedure is notA practical in the-laststeplwith dilute solutions of relatively water-#insoluble inorganic'bases such as alkaline-earth metal'hydroxides.VA

The installations which are required for'drying the vvater-solubley salt solutions 4ofi much higher concentrations are already ver-y: cumbersome.l As these solutions have la tendency'tofoamxon boiling, evaporation must proceedvery slowly. Hence excessive time vwould 'berequired in( concentrating highly dilute, relatively water-insolublesalt'solutions by this method. Moreovergit wouldnot be possible to introduce the standard charge of l100,- 000 Oxford units (see'articlelbylorey and Jennings in British Journal of Experimental Pathology, Volume 23, pageV 120,' ofi June; r1942)` into standard arnpules when 'using such relatively highly dilute solutions.

Despite these adverse" factors; the calciumsalt of penicillin is preferred over the sodium form due to the greaterstability and-lower `relative toxicity ci the former. However, `aY strong interest has prevailed for the manufacture'of the calcium'salt.

Previously, in order to overcome the stated diiculties, slaked limewasadded directly with water, or in thev form ofranaqueous slurry, to the organic I solvent containingV the' penicillin so that a iinal'aqueoussolutionof'lltheA calcium salt of penicillin could bev obtained of sufficient concentration to be charged directly tothe ampules for sublimation. of the bulk of 'thewateix In a continuous process these' procedures also had their disadvantages,namely'that the rateof iiowy i. e. the purnpability and passage through rotameters, etc., and the iconcentration of thecalcium oxide or of the calcium hydroxide could not be easily controlled to prevent an excess of calcium base in the nal product whichfexcess if present would quickly deactivate* the penicillin asso'- ciated therewith. On the other'hand, with insufficient calcium base, penicillin is rleftbehi'nd in the solventY and the aqueous penicillinsolution` is unstable.

It has now been discovered thatA dilute aqueous solutions ci penicillin alkaline-'earthmetal salts can be concentrated rapidlytoi produce salt Asolutions of high potencyand stability which, when lled into ampules,f can be evaporated' to dryness in a relatively short time-under low subatmospheric pressure witho" t resortingto arsolid base (or a slurry thereof) -by thecombin'ation of steps Inf this manner processing be most efficiently uti- 'enicillin These steps comdisclosed hereinafter. time and equipment-can lized with no loss ofV prise: (1) extraction of the penicillin from its organic solvent solution with a true aqueous solution of an alkaline-earth metal base to produce two phases: an organic solventl phase and an aqueous phase containing the corresponding penicilin salt and (2) flash vaporizing the bulk of the water from' the aqueous phase by recirculating it through a flash evaporator. The resulting concentrate, if then desired, may be introduced directly into an ampule for final sublimation.

As a consequence of this invention, one can use a dilute solution of an aqueous alkali-earth metal I basic compound instead of a slurry of an alkaline earth metal oxide whereby local high concentrations of base are avoided with the concomitant avoidance of the deactivation of the penicillin. Another advantage of being able to use such a dilute solution for the extraction is that a better and more complete extraction of the penicillin from the organic solvent solution may be obtained because of the better phase ratio.

In order to better illustrate the process of this invention, reference is had to the accompanying drawing which shows a' schematic flow diagram of an vembodiment of the invention for recovering penicillin from its solution in an organic solvent such as chloroform and/ or methyl isobutyl ketone, amyl acetate, acetone, and concentrating the recovered aqueous solution thereof.

In the drawing, -the organic solvent solution of penicillin is introduced into the mixer I through valved line I I where it is admixed with an aqueous solution of calcium hydroxide introduced through line I`2. The resulting mixture is then passed through line I3 to settler I5 wherein the aqueous phase and solvent phase are separated. The s01- Vent phase, which may still contain a small portion of the penicillin, may be Withdrawn through bottom line I6 into mixer 20 where it is again admixed with more aqueous base introduced through line 22. The resulting mixture is then passed through lline 23 into settler 25 from which the solvent is withdrawn vthrough bottom line 26, and maybe recovered for use again in the previous extraction of the penicillin from aqueous solutions. The aqueous phase removed from' the top of settler `25 may be passed through line 24 which joins with line lI2 entering mixer- I0 or a portion or all thereof may be passed through line 26 into surge tank 30. In this manner a countercurrent two-stage extraction is obtained. These mixers and settlers may be replaced by a countercurrent liquid-liquid extraction column if desired.

The resulting aqueous solution of the inorganic salt of penicillin is withdrawn from the top of the settler I through line I4 and is introduced into the surge tank 30 from which it is continuously or intermittently withdrawn through valved line 3| into the liquid recycle line 4| and thence into the heat exchanger 40 of the concentrator 50. Circulation of the aqueous solution in the concentrator Ellis based on the principle of a thermosyphon. The heat exchanger comprises a series of tubes or similar means for yindirect heat exchange of the aqueous penicillin solution with a suitable heat transfer medium. In this case, the heat transfer medium' is introduced through line 43, passes down through the vertical tubes in the chamber on the left-hand side of the heat exchanger 40 and up through the vertical tubes on the right-hand side thereof, out through line 44 and into the bottom inlet of the bottom inlet 45 of the jacket around the chamber and out of the jacket through top outlet line 46.

In the heat exchanger 40, the aqueous solution .4 is heated to a vaporizing temperature and passed' through upper vapor line 5I into ilash chamber 55 where the vapors rise through the vapor knockback section 56 and are withdrawn through line 51 into the evacuating means 60. The aqueous solution is circulated through the concentrator until it is of suflicient concentration to be charged directly into the ampules. At this time it is Withdrawn through bottom valve line 53 and charged to said ampules for evaporation to dryness by sublimation as the final penicillin salt product.

Since penicillin decomposes very easily at temperatures above about 0 C. it is desirable that the described operations be carried out as close to 0 C. as possiblewithout freezing the water present and be below about 20 C. In the concentrator 50, the aqueous solution of penicillin salt is continuously and rapidly circulated or agitated to maintain uniform conditionsgthroughout the solution, whereby heat transfer is improved and local hot spots and precipitation are prevented. The indirect heating medium employed in heat exchanger 40 may be of any suitable type such as water, alcohol, brine solutions, which are stable under the operating conditions and is at a temperature slightly higher (preferably under 50 C. and especially below 30 C.) than the circulating solution of penicillin salt. n

The evacuating means 60 may comprise a steam evacuator, or may be a carbon dioxide-cooled condenser in series with an oil vacuum pump, or may be any other suitable means for maintaining a sufficiently low pressure in the concentrator to vaporize water at the temperature maintained in the concentrator 50. -For penicillin, the pressure is maintained between about 4.5 and 20 mm. of mercury, and preferably between about 5 and 6 mm. of mercury.

The operation of the concentrator 50 may be batchwise or continuous. As a rule, batch operation is preferred when control of continuous operation is difficult due to the long time required for assaying the strength of the solution. Normally, the content of penicillin in a charge is determined and the volume of the concentrate having the desired 'strength is calculated. Then the charge is circulated through the apparatus until the calculated volume of the concentrate has been reached.

When batch operation is resorted to, one may use the Water flushing line 59 for Washing out the knockback section 56 after a batch has been sufliciently concentrated.

Example 60 liters of chloroform containing 1,405 Oxford units of penicillin per ml. Were extracted in a two-stage mixer and settler system as shown in the drawing, with an aqueous saturated solution of calcium hydroxide. The resulting 10.28 liters of aqueous phase assayed 7,960 Oxford units of the calcium salt of penicillin per ml. This aqueous solution was then circulated through a concentrator as shown in the drawing, until the aqueous solution was concentrated to a volume of a strength corresponding to 45,000 Oxford units of the calcium salts of penicillin per ml. The indirect heating medium in the heat exchanger 40 was water which was maintained at a temperature of 24 C. and maintained a temperature of about 20 C. in the aqueous solution in the concentrator 5U. An absolute pressure of about 17 mm. of mercury was maintained in the ash chamber by an oil pump connected to line 51 through a cold-trap.

The invention claimed is:

1. A process for producing an alkaline-earth metal salt of penicillin from its solution in an organic solvent comprising intimately contacting said organic solvent solution with an aqueous solution of an inorganic alkaline-earth metal base to produce an organic solvent phase and an aqueous phase containing the bulk of the said penicillin as an alkaline-earth metal salt, separating said phase, circulating said aqueous phase through a iiash vaporizing zone until a major portion of the water content is evaporated from said aqueous phase, and withdrawing the resulting aqueous concentrate from said circulating system.

2. The process of claim 1, wherein said base is calcium hydroxide.

3. The process of claim 1, wherein said aqueous solution which is initially contacted is saturated with the inorganic alkaline-earth metal base.

4. A process for producing an alkaline-earth metal salt of penicillin from an organic solution of penicillin, comprising countercurrently contacting said solution with an aqueous solution of an inorganic alkaline-earth metal base to produce an organic solvent phaseand an aqueous phase containing the bulk of the salt of penicillin corresponding to said base, separating said phases, flash evaporating a portion of the water content of said aqueous phase by circulating it through a heating zone in indirect heat exchange with a heat transfer medium and through a vapor disengaging zone maintained at a suiiciently low pressure to evaporate at least a portion of the water from said vapor withdrawing the resulting concentrate of the alkaline-earth metal salt of penicillin from the circulating system.

5. The process of claim 4, wherein said heat transfer medium is between about 0 C. and 50 C.

6. The process of claim 4, wherein said pressure iS below about mm. of mercury.

7. The process of claim 4, wherein said alkalineearth metal base is calcium hydroxide.

8. A process for producing and concentrating a salt of penicillin comprising contacting a solution of penicillin in an organic solvent with an aqueous solution of an inorganic alkaline-earth metal base to produce an organic solvent phase and an aqueous phase containing an alkalineearth metal salt of penicillin, separating said solvent phase from said aqueous phase, flash evaporating a portion of the water content from said aqueous phase by circulating it through a heating zone in indirect heat exchange with a heat transfer medium having a temperature below about C. and through a. vapor disengaging zone maintained at a sufficiently low pressure to cause said evaporation to take place below about 30 C., continuing said circulation until a major amount of the water content is evaporated during each cycle, and f maintained at a temperature l from said aqueous phase, and withdrawing the resulting concentrate of the penicillin salt from the circulating system.

9. A process for producing an alkaline-earth metal salt of penicillin from its solution in an organic solvent, comprising contacting said organic solvent solution with an aqueous solution of an alkaline-earth metal hydroxide to produce an organic solvent phase and an aqueous phase containing the bulk oi the penicillin as an alkaline-earth metal salt, separating said phases, circulating said aqueous phase through a ash vaporizing zone until a major portion of the water content is evaporated from said aqueous phase, withdrawing the aqueous concentrate from said circulating system and introducing it into a container, and subliming the remaining water from said concentrate to produce a substantially dry alkaline-earth metal salt of said organic solute in said container.

10. A process for producing an alkaline-earth metal salt of penicillin from an organic solution containing penicillin, comprising the steps of intimately contacting said organic solution with an zqueous solution of an alkaline-earth metal hydroxide to produce an organic solvent phase and an aqueous phase containing the bulk of said penicillin, separating the phases, circulating said aqueous phase through a heating zone wherein the aqueous phase is heated by indirect heat exchange with a, heat transfer medium maintained at a temperature between about 0 C. and 50 C. and through a flash vaporizing Zone while maintaining within said zone a temperature between about 0 C. and 20 C., and a pressure below about 20 mm. of mercury, and withdrawing the resulting concentrate of the alkaline-earth metal sait of penicillin from the circulating system.

11. The process according to claim 10 wherein the heat transfer medium is maintained at a temperature below 30 C.

12. The process according to claim 10 wherein the aqueous solution of a basic-acting alkalineearth metal compound is substantially saturated solution of calcium hydroxide.

CLARENCE L. DUNN. MOTT SOUDERS, Je. CORNELIUS GRCOT.

REFERENCES CITED The following references are of record in the le of this patent:

UNITED STATES PATENTS Number Name Date 1,438,502 Peebles Dec. 12, 1922 2,076,597 Robinson Aug. 13, 1937 OTHER REFERENCES Abraham, British J. of Exp. Path., vol. 23, June 1942, No. 3, pp. 103-114. 

